Identification of small-molecule inhibitors targeting the PD-1/PD-L1 interaction in colorectal cancer: insights from docking and molecular dynamics simulations

The PD-1/PD-L1 axis promotes tumour immune evasion and functions as a crucial immune checkpoint, highlighting its importance as a primary target for immunotherapy in colorectal cancer. Although there have been significant improvements in the use of antibodies to treat colorectal cancer, therapeutic antibodies still face several challenges, including immune responses and immunologically mediated toxicities. Natural compounds are emerging as attractive small-molecule inhibitors of PD-L1 and enhancers of anticancer T cell-mediated responses. We reviewed the marine natural products database to identify potential lead compounds for developing new small-molecule inhibitors targeting the PD-1/PD-L1 axis. Among the compounds examined, CMNPD3605 demonstrated the most powerful inhibition of PD-1/PD-L1 interaction and showed greater promise than current small-molecule inhibitors in clinical studies. In conclusion, this study identifies novel PD-L1 inhibitors and sets up a computational framework for making small-molecule immune checkpoint inhibitors that can be tested in living colorectal cancer models.